Cancer remains a significant health problem throughout the world. Current therapies, which are generally based on a combination of chemotherapy or surgery and radiation, continue to prove inadequate in many patients.
The molecular and cell biology of cancer is enormously complex. To date, thousands of genes representing virtually every sub-group of genes have been implicated in the pathophysiology of cancer, including mechanisms regulating uncontrolled growth of tumor cells and metastasis. Currently, it is well established that many cancers, if not all, develop from proliferating stem or progenitor cells with either mutated genes or rearranged chromosomes. As a result of these genetic alterations, tumor cells possess an altered gene and protein expression compared with normal cells (Perou et al., 2000, Hedenfalk et al., 2001, West et al., 2001, Zajchowski et al., 2001). Furthermore, differences in gene expression exist between different types of the same cancer or between histologically similar tumors. For example, data on whole-genome analyses have demonstrated that regulatory networks that determine the expression of specific genes are also different in malignant and non-malignant cells.
Regulation of gene expression at the transcriptional level is a key biological process in determining cell-type and signal-specific gene expression patterns. The above objectives are mainly focused on proteins forming the regulatory networks that control fundamental biological processes in normal and cancer cell contexts Successful execution of cell-specific gene regulation, which combines interdisciplinary efforts, promises new breakthroughs in the field of transcription regulation and cancer, since they address novel aspects in the process, including:                the specific functions of individual basal. RNA polymerase II transcription complexes and how they participate in regulation of gene expression in normal and cancer cells;        how gene specific transcription is achieved during cell differentiation in normal and cancer cells; and        how the normal and cancer cell transcription process is spatially organized in the nucleus.        
We postulate that a virtually infinite number of transcriptional complexes can recruit the basal transcription machinery in a gene-specific manner to regulate precisely the expression of genes during differentiation, growth and development in response to external signals (drugs, chemicals, stress etc). The materials and methods disclosed herein serve to decipher how these transcription complexes are deregulated in cancer cells.
Precise temporal and spatial regulation of the transcription of protein-encoding genes by RNA polymerase II (Pol II) is vital to the execution of cellular programs, such as growth, responses to complex developmental and homeostatic signals etc. The molecular circuitry that enables coordinated gene expression is based on DNA-binding transcription factors (TFs) and several transcription co-regulator complexes (TCCs) that modulate chromatin structure and bridge TFs to PolII including, SWI/SNF, MED, GTF and TAF-containing complexes. Numerous data show that different cell types including cancer cells express specific patterns of components of TFs and TCCs. Cell type specific expression of components of TCCs (and their isoforms) is the basis of assembly of transcription complexes with different functions. Different transcription complexes target different sets of DNA binding factors leading to inactivation of different target gene sets and ultimately to realization of different cellular programs.
One of the well-known characteristics of cancer cells is the expression of mRNA splice variants encoding specific isoforms of proteins that are not present in normal cells. A large number of studies report identification of cancer specific or enriched mRNA alternative splice variants. For example, a genome-wide computational screening of 11,014 genes using 3,471,822 human expressed sequence tag (EST) sequences identified 26,258 alternatively spliced transcripts/mRNAs of which 845 were significantly associated with cancer (Wang et al., 2003). Several of the gene-specific splice variants have been shown to have a prognostic value. High level of expression of low molecular weight isoforms of cyclin E has a very strong correlation with survival of both node-negative and node-positive breast cancer patients (Porter and Keyomarsi, 2000, Keyomarsi et al., 2002). Patients with a high expression of the alternative splice variant of helix-loop-helix transcription factor ARNT have a worse relapse-free and overall survival than patients with a low expression (Qin et al., 2001).
Computational analysis of human EST databases identified a large number of mRNA splice variants of regulatory factors (TCCs) that are expressed in a variety of cancer cells. The present invention is based on in silico analysis using a variety of gene expression and EST databases, which has revealed a large number of alternative splice variants of (TCCs) that have cell type and disease specific expression. Splice variants encoding protein isoforms are expressed in cancer cells as relatively abundant isoforms. These isoforms modify transcriptional machinery that results in altered gene expression and may contribute to the development of cancer.
The central role of the transcriptional complexes in the cellular regulatory mechanisms makes them attractive drug targets. Interference at the function or formation of cancer-specific transcription machinery could enable researchers and clinicians to control or correct expression of a large number of genes. TCCs contain at least 100 subunits, whereas their composition in different cell types and on different promoters varies and contains different members of TCC complexes. This cell specific variability of TCC complexes assures specificity of potential treatments that target TCCs. We have isolated a large number of isoforms of components of TCCs with a potentially altered activity from a variety of cancer cells. TAF-containing complexes have been shown to control several aspects of cancer cell proliferation and metastasis (Guipaud et al., 2006). In addition, several isoforms of TAF4 function as dominant negative forms to regulate nuclear hormone receptor targets (Brunkhorst et al., 2004).